Diazabicyclodecanes as anti-ulcer agents

ABSTRACT

Certain bridged 1,5-diazacyclodecanes, e.g., 9-phenyl-1,5diazabicyclo(4.3.1)decanes are useful as anti-ulcer agents.

United States Patent [191 Boyajy et a].

[111 3,867,532 [451 Feb. 18, 1975 DIAZABICYCLODECANES AS ANTI-ULCER AGENTS [75] inventors: Louis D. Boyajy, Parsippany; John H. Gogerty, Dover, both of NJ.

[52] U.S. Cl. 424/251 [51] Int. Cl A61k 27/00 [58] Field of Search 424/251 [5 6] References Cited UNITED STATES PATENTS 3,517,004 6/1970 Houlihan 424/251 Primary ExaminerFrederick E. Waddell Attorney, Agent, or FirmGerald D. Sharkin; Robert S. Honor; Thomas O. McGovern [5 7] ABSTRACT Certain bridged 1,5-diazacyclodecanes, e.g., 9-phenyll,5-diazabicyclo[4.3.1 ]decanes are useful as anti-ulcer agents.

6 Claims, N0 Drawings tions containing the above compounds as an active ingredient thereof.

The active agents with which this invention is concerned may be represented by the following structural formula:

where R is hydrogen, fluoro, chloro or lower alkoxy, i.e., alkoxy having 1 to 4 carbon atoms, e.g., methoxy, ethoxy, isopropoxy and the like, or pharmaceutically acceptable salts thereof.

This invention contemplates only the novel use of the compounds of formula (I) in the treatment of ulcers and pre-ulcer conditions such as severe irritation of the gastrointestinal track.

Many of the compounds of formula (1) above are known and may be prepared according to methods disclosed in the literature, for example, in US. Pat. No. 3,517,004. The compounds not specifically disclosed in the literature may be prepared by analogous methods using known starting materials.

The pharmaceutically acceptable salts include the non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared in conventional manner by reacting the base with the appropriate acid and are included within the scope of the invention. Representative of the acid addition salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulphate phosphate and the like, and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate and the like.

The use of the compounds of formula (I) as antiulcer agents is suggested by their autonomic profile as indicated by blood pressure changes in the anesthetized dog given 1 to milligrams per kilogram of test compounds intravenously as measured with the aid of a mercury manometer or transducer via a catheter inserted in either the carotid or femoral artery of the animal and recorded either on a kymograph or an appropriate electronic recorder. The surgical method of preparing the animal is a modification of that described by Markowitz (Exper. Surgery, Williams and Wilkins, 2nd Ed., 1949). The inhibition of the depressor response (fall in blood pressure) to vagal stimulation using a Grass stimulator shows a suppression of the release of acetylcholine at the parasympathetic postganalionic neuroeffector sites and indicates the compounds of formula (I) are useful in the treatment of ulcers.

The anti-ulcer activity of the compounds of formula (I) is indicated by the prevention of stress induced ulcers produced by cold confinement at 4C in rats given one milligram per kilogram per hour of the test compound using a modification of the technique of Brodie, D. A., et al. (Gastroenterology 38; 353. i960) and by the inhibition of gastrointestinal motility produced by vagal stimulation using a Grass stimulator in the anesthetized dog given 1 to 10 milligrams per kilogram of the test compound according to the method of Craver, B. M., et al (J. Pharmacol and Exp. Ther. 93. 168, 1948). I

For such usage, the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered in such forms tablets, dispersible powders, granules, capsules, syrups and elixirs ancl parenterally as solutions, suspensions, dispersions, emulsions and the like, e.g., a sterile injectable aqueous suspension. The compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g, starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, oral liquids, e.g., suspensions maycontain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose tragacanth and sodium alginate) wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan mono-oleate)'and preservatives (ethyl-o-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about percent of the active ingredient in combination with the carrier or adjuvant.

The anti-ulcer effective dosage of the compounds of formula (I) employed in the treatment of ulcers and pre-ulcer conditions may vary depending on the particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of formula (I) are administered at a daily dosage of from about 1 milligrams to about I00 milligrams per kilogram of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 60 milligrams to about 1500 milligrams. Dosage forms suitable for internal use comprise from about 15 to about 750 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hardfilled capsules and tablets containing from about 100 to 250 milliln a similar manner, injectable suspensions and liquid suspensions may be prepared using 9-(pchlorophenyl)- l ,5-diazabicyclo[4.3.l ]decane or 9-( pmethoxyphenyl)-l ,5-diazabicyclo[4.3. l ]decane as the grams of the active ingredient. 5 active ingredient in place of the 9-phenyl-l .5-

EXAMPLES I and 2 diazabicyclo[4.3.l]decane above. Tablets and Capsules Suitable For Oral Administration EXAMPLE 5 Tablets and capsules containing the ingredients indi- St il S l i f Injectign cated below may be prepared by conventional tech- 10 The following ingredients are dissolved in water for "lques and are useful in treating ulcers at a dose Of One injection and the resulting solution is filtered through tablet Capsule 2 to 4 times a ym, an appropriate medium to form a clear solution which is then sterilized. The sterile injectable solution is suitlngrediems Weight (mg) able for administration once or twice a day in the treat- 15 ment of ulcers or pre-ulcer conditions. tablet capsule 9-phenyl-l ,5-diazabicyclo[4.3.l] I 100 decane hydrochloride tragacanth l0 lactose 247.5 200 corn starch 25 2O lngredlem Weigh! g talcum l5 mugncgium curate 3,5 9-phenyl-l.5-diazacyclol4.3.l]decane Total 400 mg. 300 mg. ydrochloride 10 V Sodium alginate In a similar manner, tablets and capsules may be prelffigflii as a pared using 9-(p-chlorophenyl)-l,5- Sodium l r as desired diazabicyclo[4.3.l ]decane or 9-(p-methoxyphenyl)- for m l l,5-diazabicyclo[4.3. l ]decane as the active ingredient in place of the 9-phenyl-l,5-diazabicyclo[4.3.1] dec ane above. Similar injectable solutions for injection may be prepared using 9-( p-chlorophenyl )-l ,5-

EXAMPLES 3 and 4 diazacyclo[4.3.l ]decane hydrochloride or 9-(p- Sterile Suspension for Injection and Oral Liquid Suschlorophenyl)-l,5-diazabicyclo[4.3.l]decane hydropension chloride in place of the 9-phenyl-l,5-

The following pharmaceutical compositions are fordiazabicyclo[4.3.l]decane hydrochloride above. mulated with the indicated amount of active agent using conventional techniques. The injectable suspen- EXAMPLE 6 sion and the oral liquid suspension represent formula- Syrups and Elixirs for Oral Administration tions useful as unit doses and may be administered in The following formulations for syrups or elixirs conthe treatment of ulcers. The injectable suspension is taining an effective amount of active compound may be suitable for administration once or twice aday whereas formulated using conventional methods and are suitthe oral liquid suspension is suitably administered 2 to able for administration 2 to 4 times a day in the treat- 4 times per day for this purpose. ment of ulcers and pre-ulcer conditions.

Ingredients eig g) liquid suspension 9-phenyll .5-diazabicyclo[4.3.l ]decane 200 I00 sodium carboxy methyl cellulose U.S.P. l.25 12.5 methyl cellulose 0.4 polyvinylpyrrolidone 5 lecithin 3 benzyl alcohol 0.0] magnesium aluminum silicate 47.5 flavor q.s. color q.s. methyl parahen. U.S.P. 4.5 prbpyl paraben. U.S.P. [.0 polysurbatc 80 {c.g. Tween 80), USP 5 sorhitol solution, USP 2,500 buffer agent to adjust pH for desired stability q.s. q.s. water for injection q.s. to 5 ml.

q.s. to l ml.

Ingredient Percent by Weight syrup elixir 9-phenyl-l ,5-diazabicyclo[4.3.l ]decane hydrochloride .53.5 .53.5 Buffering system quantity sufficient to adjust pH Sodium henzoate .l.5 l.5 Flavoring agent .0l.2 .0l.2 Water 2040 5-20 Analogous compositions to those above may be prepared using the hydrochloride salt of 9-(pchlorophenyl)-1,5-diazabicyclo[4.3.l]decane or 9-(pmethoxyphenyl)-l ,5-diazabicyclo[4.3.l ]decane in place of the 9-phenyl-1,5-diazabicyclo[4.3.l]decane hydrochloride.

What is claimed is:

l. A method of treating gastrointestinal ulcers in a mammal, which comprises administering thereto an antr-ulcer effective amount of a compound of the formula:

where R is hydrogen, fluoro, chloro or lower alkoxy or a pharmaceutically acceptable acid addition salt thereof.

2. The method of claim 1 wherein the compound is administered at a daily dosage of from about 60 milligrams to about 1500 milligrams.

3. The method of claim 1 wherein the compound is administered in a unit dosage form comprising from about 15 milligrams to about 750 milligrams of said compound per unit dosage.

4. The method of claim 1 in which the compound is 9-phenyl-l ,5-diazabicyclo[4.3. l ]decane 5. The method of claim 1 in which the compound is 9-(p-chlorophenyl)1 ,5-diazabicyclo[4.3. l ]decane.

6. The method of claim 1 in which the compound is 9-(p-methoxyphenyl)-l ,5-diazabicyclo[4.3.l ]decane. 

1. A METHOD OF TREATING GASTROINTESTINAL ULCERS IN A MAMMAL, WHICH COMPRISES ADMINISTERING THERETO AN ANTI-ULCER EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
 2. The method of claim 1 wherein the compound is administered at a daily dosage of from about 60 milligrams to about 1500 milligrams.
 3. The method of claim 1 wherein the compound is administered in a unit dosage form comprising from about 15 milligrams to about 750 milligrams of said compound per unit dosage.
 4. The method of claim 1 in which the compound is 9-phenyl-1,5-diazabicyclo(4.3.1)decane.
 5. The method of claim 1 in which the compound is 9-(p-chlorophenyl)1,5-diazabicyclo(4.3.1)decane.
 6. The method of claim 1 in which the compound is 9-(p-methoxyphenyl)-1,5-diazabicyclo(4.3.1)decane. 